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The atypical cadherin MUCDHL antagonizes colon cancer formation and inhibits oncogenic signaling through multiple mechanisms

Abstract

Cadherins form a large and pleiotropic superfamily of membranous proteins sharing Ca2+-binding repeats. While the importance of classic cadherins such as E- or N-cadherin for tumorigenesis is acknowledged, there is much less information about other cadherins that are merely considered as tissue-specific adhesion molecules. Here, we focused on the atypical cadherin MUCDHL that stood out for its unusual features and unique function in the gut. Analyses of transcriptomic data sets (n > 250) established that MUCDHL mRNA levels are down-regulated in colorectal tumors. Importantly, the decrease of MUCDHL expression is more pronounced in the worst-prognosis subset of tumors and is associated with decreased survival. Molecular characterization of the tumors indicated a negative correlation with proliferation-related processes (e.g., nucleic acid metabolism, DNA replication). Functional genomic studies showed that the loss of MUCDHL enhanced tumor incidence and burden in intestinal tumor-prone mice. Extensive structure/function analyses revealed that the mode of action of MUCDHL goes beyond membrane sequestration of ß-catenin and targets through its extracellular domain key oncogenic signaling pathways (e.g., EGFR, AKT). Beyond MUCDHL, this study illustrates how the loss of a gene critical for the morphological and functional features of mature cells contributes to tumorigenesis by dysregulating oncogenic pathways.

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Fig. 1: Reduced expression of MUCDHL in human colon tumors is an adverse event.
Fig. 2: Loss of Mucdhl expression enhances intestinal tumorigenesis in mice.
Fig. 3: MUCDHL M antagonizes the transcriptional activity of ß-catenin by multiple mechanisms.
Fig. 4: The extracellular region of MUCDHL M inhibits ß-catenin by interfering with EGFR signaling.
Fig. 5: MUCDHL M can enhance the proteasome-mediated degradation of ß-catenin.
Fig. 6: Both intracellular and extracellular domains of MUCDHL M have antitumor potential.

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Acknowledgements

The authors thank Drs. C. Perret, M. Rousset, H. Clevers, E. Fearon, A. Sorkin, B. Gumbiner, and A. Jung for reagents.

Funding

This work was supported by the financial support of INSERM (2013–2019), Fondation ARC (#SFI20101201854), and La Ligue Contre Le Cancer (Haute-Marne 2013, Haut-Rhin 2016); MBe, MBa, EB, AMS, and IH were fellows of the French government (Ministère de l’Enseignement Supérieur et de la Recherche). MBe and MBawere also fellows of Fondation ARC, and EB of the FRM.

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Correspondence to Isabelle Gross.

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Beck, M., Baranger, M., Moufok-Sadoun, A. et al. The atypical cadherin MUCDHL antagonizes colon cancer formation and inhibits oncogenic signaling through multiple mechanisms. Oncogene 40, 522–535 (2021). https://doi.org/10.1038/s41388-020-01546-y

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